Women who had a pregnancy lasting more than 20 weeks after receiving fertility treatments did not have a greater cardiovascular risk over about the next decade compared with women who conceived without assistance, researchers found.

In fact, after adjustment for differences in baseline characteristics, the women who were treated for infertility had a significantly lower risk of death or hospitalization for a major adverse cardiovascular event over a median follow-up of 9.7 years (HR 0.55, 95% CI 0.41-0.74), according to Jacob Udell, MD, MPH, of the University of Toronto, and colleagues.

That finding -- reported online in the Journal of the American College of Cardiology -- was based on just 44 outcome events in women who underwent fertility treatment (versus 12,730 in the rest of the cohort), and the authors noted that the results should be interpreted with caution.

But, they wrote, "The current findings provide some reassurance that fertility therapy does not appear to increase long-term risk of cardiovascular events following successful pregnancy."

Although fertility therapy can be effective for achieving pregnancy and is now associated with about 1% of all births in North America, it may have some unintended consequences. Previous studies have highlighted concerns about a heightened cardiovascular risk stemming from maternal metabolic syndromes, direct endothelial dysfunction, and prothrombotic effects.

To explore the issue, the researchers turned to the GRAVID study, a population-based cohort analysis of women ages 15 to 55 (mean age 29) who had a pregnancy lasting more than 20 weeks and who gave birth in Ontario from July 1, 1992, through March 31, 2010. The patients were identified through the Ontario Health Insurance Plan.

The current study included 1,186,753 women; 6,979 (0.6%) received fertility treatment in the 2 years before delivery.

Adjusted analysis showed that in the short term, the women who had received treatment for infertility were more likely than the others to develop the following:

gestational diabetes (OR 1.29, 95% CI 1.17-1.41)

serious placental complications (OR 1.16, 95% CI 1.04-1.29)

pre-eclampsia (OR 1.10, 95% CI 1.01-1.20)

preterm threatened labor (OR 1.41, 95% CI 1.31-1.52)

ovarian hyperstimulation syndrome (OR 3.29, 95% CI 2.37-4.57)

urinary tract infections (OR 1.22, 95% CI 1.08-1.40)

Over the long term, however, receipt of fertility treatment was associated with a lower rate of death or hospitalization for major adverse cardiovascular events, including nonfatal coronary ischemia, stroke, transient ischemic attack, thromboembolism, and heart failure (103 versus 117 events per 100,000 person-years).

The difference remained significant after adjustment for age, year of delivery, demographics, baseline medical history and obstetrical characteristics, length of stay, and short-term pregnancy complications, and was consistent across age and income groups.

The lower risk was seen for all-cause mortality (HR 0.50. 95% CI 0.31-0.80) and thromboembolism (HR 0.45, 95% CI 0.21-0.94), but there were no differences between the groups for the other components of the endpoint.

Udell and his colleagues noted that the reason for the lower risk observed in the women who underwent treatment for infertility remains unclear, but proposed three possible explanations: women with fertility problems adopt healthier lifestyles following successful deliveries, women with poorer health do not choose to receive fertility treatments, or fertility treatments are biologically protective.

The most likely candidate from that list is that women opt for healthier habits after a successful delivery, according to Jolien Roos-Hesselink, MD, PhD, of Erasmus Medical Center in Rotterdam, and Mark Johnson, MD, PhD, of Imperial College London.

"However," they wrote in an accompanying editorial, "this would be very difficult to prove."

They pointed out some methodological issues with the analysis, including the difficulty in adjusting for some of the large, between-group differences in baseline characteristics -- age, for example -- and the lack of information on women who underwent unsuccessful treatment for infertility, who may have received higher cumulative doses of hormones.

"The current data are reassuring, as they suggest that fertility treatment does not itself increase the risk of cardiovascular events or risk factors and may actually have a direct or indirect beneficial effect," Roos-Hesselink and Johnson wrote, "but overall we should remember that the population needing fertility treatment is actually at increased risk of cardiovascular and metabolic disease."

The study authors acknowledged some limitations of their analysis, including the inability to examine specific medications, doses, or strategies for individual patients, the possibility of missing clinical data, and the potential for residual confounding by unmeasured factors.

The study received support from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Canadian Foundation for Women's Health, CHEST Foundation, Respiratory Health Association of Metropolitan Chicago, and a Canada Research Chair in Medical Decision Sciences.

The study authors and the editorialists reported that they had no conflicts of interest.

Reviewed by Zalman S. Agus, MD Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner